Marine-Derived Macrocyclic Alkaloids (MDMAs): Chemical and
Biological DiversityMarine-Derived Macrocyclic Alkaloids (MDMAs):
Chemical and Biological Diversity
Hanan I. Althagbi 1,2, Walied M. Alarif 3,*, Khalid O. Al-Footy 2
and Ahmed Abdel-Lateff 4,5
1 Department of Chemistry, Faculty of Science, University of
Jeddah, P.O. Box 13151, Jeddah 21493, Saudi Arabia;
[email protected]
2 Department of Chemistry, Faculty of Science, King Abdulaziz
University, P.O. Box 80203, Jeddah 21589, Saudi Arabia;
[email protected]
3 Department of Marine Chemistry, Faculty of Marine Sciences, King
Abdulaziz University, P.O. Box 80207, Jeddah 21589, Saudi
Arabia
4 Department of Natural Products and Alternative Medicine, Faculty
of Pharmacy, King Abdulaziz University, P.O. Box 80260, Jeddah
21589, Saudi Arabia;
[email protected]
5 Department of Pharmacognosy, Faculty of Pharmacy, Minia
University, Minia 61519, Egypt * Correspondence:
[email protected]; Tel.: +966-5603-520-34
Received: 14 May 2020; Accepted: 15 July 2020; Published: 17 July
2020
Abstract: The curiosity and attention that researchers have devoted
to alkaloids are due to their bioactivities, structural diversity,
and intriguing chemistry. Marine-derived macrocyclic alkaloids
(MDMAs) are considered to be a potential source of drugs.
Trabectedin, a tetrahydroisoquinoline derivative, has been approved
for the treatment of metastatic soft tissue sarcoma and ovarian
cancers. MDMAs displayed potent activities that enabled them to be
used as anticancer, anti-invasion, antimalarial, antiplasmodial,
and antimicrobial. This review presents the reported chemical
structures, biological activities, and structure–activity
relationships of macrocyclic alkaloids from marine organisms that
have been published since their discovery until May 2020. This
includes 204 compounds that are categorized under eight subclasses:
pyrroles, quinolines, bis-quinolizidines, bis-1-oxaquinolizidines,
3-alkylpiperidines, manzamines, 3-alkyl pyridinium salts, and
motuporamines.
Keywords: marine natural products; macrocyclic alkaloids; potential
drugs; biological activity
1. Introduction
The marine environment is one of the harshest atmospheres on the
earth due to its diverse ranges of light, temperature, pressure,
and nutrient circumstances [1]. These conditions enable marine
organisms to produce extremely different and unprecedented
metabolites with a wide range of bioactivities [2,3]. The organisms
that live in this environment have immense genetic and biochemical
diversity that, being the source of unexplored bioactive products,
could be beneficial for the development of potential drugs
[4].
The discovery of such drugs is expensive, time-consuming, and risky
because it is achieved through complicated processes. Moreover,
drug discovery is supported by the combination of databases with
dereplication methodologies, such as computer-assisted structure
elucidation (CASE) and mass spectrometry or nuclear magnetic
resonance (NMR) spectroscopy (metabolite- guided and genome-guided
approaches) [3].
Twenty marine-derived compounds have been considered in different
clinical trial phases, ranging from Phase I to III. Moreover, four
macrocyclic compounds out of eight approved marine-derived drugs
have been approved by the Food and Drug Administration (FDA),
Australia’s Therapeutic Goods Administration, the European
Medicines Agency (EMA), and the Japanese Ministry of Health
[5].
Mar. Drugs 2020, 18, 368; doi:10.3390/md18070368
www.mdpi.com/journal/marinedrugs
Marine macrocyclic natural products (MMNPs) include four main
subclasses according to their structural differences, namely,
cyclic depsipeptides, diterpenes, macrolides, and macrocyclic
alkaloids. MMNPs have been reported from different sources,
including sponges, algae, fungi, mollusks, cyanobacteria, and
gorgonians [6].
The unprecedented skeletons of MMNPs and structural complexity have
an important role in the potency of their bioactivities. This has
enhanced the discovery of anticancer drugs such as trabectedin [7],
which is a tetrahydroisoquinoline alkaloidal derivative that has
been approved by the FDA and the European Agency for the Evaluation
of Medicinal Products (EMEA) as an anticancer drug. Ingenamine G
has been shown to exhibit potent cytotoxic effects against HCT-8
(colon), B16 (leukemia), and MCF-7 (breast) cancer cell lines, as
well as antibacterial effects against Staphylococcus aureus,
Escherichia coli, four oxacillin-resistant S. aureus strains, and
Mycobacterium tuberculosis H37Rv [8]. The potent blocking activity
of xestospongin A, araguspongine B, demethylxestospongin B, and
araguspongines C and D on IP3-mediated Ca2+ release from the
endoplasmic reticulum vesicles of the rabbit cerebellum has been
published [9]. Finally, the antimalarial activity of manzamines has
been reported [10].
This review discusses the reported chemical structures, biological
effects, and structure–activity relationships (SARs) of eight
subclasses of marine-derived macrocyclic alkaloids-pyrroles,
quinolines, bis-quinolizidines, bis-1-oxaquinolizidines,
3-alkylpiperidines, manzamines, 3-alkyl pyridinium salts, and
motuporamines. Also included within this review are 204 compounds
that have been reported since their discovery until May 2020
(Figure 1 and Table 1).
Mar. Drugs 2020, 18, x FOR PEER REVIEW 3 of 36
Figure 1. Percentage of marine-derived macrocyclic alkaloids’
subclasses.
Pyrroles 1% Quinolines
Table 1. List of marine-derived macrocyclic alkaloids.
Compound No. Subclasses Name of Compounds Marine Organism
Biological Activities
1–2 Pyrroles Densanins A and B Haliclona densaspicula
Anti-inflammatory
3–8
Cytotoxic and Anti-HIV
11 Njaoamine I Reniera sp.
12
Bis-Quinolizidines
15 Aragupetrosine A Xestospongia sp.
16 Xestosin A
18 Xestospongin B
20 Xestospongin D (Araguspongine A) Xestospongia sp.
21–26 Xestospongins E–J Oceanapia sp.
27 (+)-7S-Hydroxyxestospongin A Xestospongia sp.
28 Demethylxestospongin B Xestospongia sp.
and Neopetrosia exigua
31 Araguspongine B
Antimicrobial and Cytotoxic
33–36 Araguspongines F–H and J Xestospongia sp.
37 3a-Araguspongin C Haliclona exigua
38–39 Araguspongines K and L Neopetrosia exigua 40 Araguspongine
M
41–43 Araguspongines N–P Xestospongia muta 44 meso-araguspongine
C
Mar. Drugs 2020, 18, 368 4 of 34
Table 1. Cont.
Compound No. Subclasses Name of Compounds Marine Organism
Biological Activities
45–47
3-Alkyl piperidines
51–53 Saraines A-C
59 Madangamine F Pachychalina alcaloidifera
60 (10E,12Z)-haliclonadiamine Halichondria panicea
62 Papuamine Haliclona sp.
65–66 Ingamines A and B
Xestospongia ingens
74 Dihydroingenamine D Petrosid Ng5 Sp5 75 22(S)-Hydroxyingamine
A
76 Xestocyclamine Xestospongia sp. protein kinase C inhibitor
77–78 Halicyclamines A-B Xestospongia sp.
Cytotoxic
81 22-Hydroxyhaliclonacyclamine B Halichondria sp.
82 2-epi-Tetradehydrohaliclonacyclamine Halichondria sp.
84 Tetradehydrohaliclonacyclamine A Halichondria sp.
85 Haliclonacyclamine C Haliclona sp.
86 Haliclonacyclamine D Haliclona sp.
87 Haliclonacyclamine E Arenosclera brasiliensis
Antimalarial,
Cytotoxic, Proteasome and
89 Halichondramine Halichondria sp.
Mar. Drugs 2020, 18, 368 5 of 34
Table 1. Cont.
Compound No. Subclasses Name of Compounds Marine Organism
Biological Activities
92–94 Arenosclerins A–C A. brasiliensis
Cytotoxic, Anti-leishmanial,
and Anti-HIV
97
Manzamines
98 8-Hydroxymanzamine A (Manzamine G) Amphimedon sp. and
Pachypellina sp.
99 3,4-Dihydromanzamine A Amphimedon sp.
100 6-Hydroxymanzamine A (Manzamine Y) Amphimedon sp. and Haliclona
sp.
101 1,2,3,4-Tetrahydro-8-hydroxymanza-mine A (8-Hydroxymanzamine D)
Cribochalina sp. and Petrosia sp.
102 1,2,3,4-Tetrahydro-2-N-methyl-8-hyd-roxymanzamine A
(8-Hydroxy-2-N-methylmanzamine D)
104 3,4-Dihydro-6-hydroxymanzamine A Amphimedon sp. 105 Manzamine
M
106 N-Methyl-epi-manzamine D Unidentified Paluan sponge 107
epi-Manzamine D
108 12,34-Oxamanzamine A Sponge 011ND 35
109 ent-8-Hydroxymanzamine A Unidentified Indo-Pacific sponge
110 12,28-Oxamanzamine A Acanthostrongylophora sp. 111
12,28-Oxa-8-hydroxymanzamine A
112 Manzamine A N-oxide Xestospongia ashmorica 113
3,4-Dihydromanzamine A N-oxide
114–115 Acanthomanzamines A and B Acanthostrongylophora sp.
116 Pre-neo-kauluamine Acanthostrongylophora ingens
Table 1. Cont.
Compound No. Subclasses Name of Compounds Marine Organism
Biological Activities
120 Ircinol A
122 Ircinal E
123 12,28-Oxaircinal A
124 Manzamine E Xestospongia sp. 125 Manzamine F (Keramamine
B)
126 ent-Manzamine F
129 12,34-Oxamanzamine E
135–136 Manzamines H, J Ircinia sp.
137 Manzamine J N-oxide Xestospongiaashmorica
138 8-Hydroxymanzamine B Acanthostrongylophora sp.
139 Manzamine L Amphimedon sp.
140 Manzamine B N-oxide Acanthostrongylophora sp.141
3,4-Dihydromanzamine B N-oxide
142 11-Hydroxymanzamine J
144 8-Hydroxymanzamine J Acanthostrongylophora
146–147 Acanthomanzamines D and E Acanthostrongylophora sp.
148–149 Zamamidines A and B Amphimedon sp.
150 Ircinal B Ircinia sp.
151 Ircinol B Amphimedon sp.
Mar. Drugs 2020, 18, 368 7 of 34
Table 1. Cont.
Compound No. Subclasses Name of Compounds Marine Organism
Biological Activities
152 Manzamine C Haliclona sp.
Cytotoxic
154 Acanthomanzamine C
159 32,33-Dihydro-6-hydroxymanzamine A-35-one
160 32,33-Dihydro-6,31-dihydroxymanzamine A
163–164 Manadomanzamines A and B Acanthostrongylophora sp.
165 Keramaphidin B Amphimedon sp.
166 Kauluamine Prianos sp.
Antimicrobial and Cytotoxic
173–177 Cyclostellettamines G–I, K, and L Pachychalina sp.
178–179 Dehydrocyclostellettamines D, E Xestospongia sp.
180 8,8‘-Dienecyclostellettamine Amphimedon compressa
181–184 Cyclostellettamines N, R, O, Q Haliclona sp.
185–192 Cyclostellettamines Haliclona sp.
193 Cyclostellettamine P Xestospongia exigua
194–196 Njaoaminiums A–C Reniera sp. Cytotoxic
197–205 Motuporamines Motuporamines A–I Xestospongia exigua
Anti-invasion
Mar. Drugs 2020, 18, 368 8 of 34
2. Macrocyclic Alkaloids
Densanins
Densanins A (1) and B (2) were isolated from the sponge Haliclona
densaspicula [11]. Densanins are fused hexacyclic diamine alkaloids
with a pyrrole ring that fused to the tricyclic core (Figure 2).
Compounds 1 and 2 displayed potent inhibitory effects against
lipopolysaccharide-induced nitric oxide production in BV2
microglial cells, with IC50 values of 1.05 and 2.14 µM,
respectively [11]. These cells are macrophages of the central
nervous system (CNS) and are considered to be a primary form of the
active immune defense in the CNS, particularly in Alzheimer’s and
Parkinson’s diseases. Microglia are chronically activated and
promote the release of cytokines, which further disrupt normal CNS
activities. Thus, the inhibitory effect of inflammatory mediator
production in these cells can mitigate the effects of inflammation.
Therefore, both metabolites could have potential for development of
drugs for treatment of neurodegenerative diseases such as
Alzheimer’s and Parkinson’s diseases [12].
Mar. Drugs 2020, 18, x FOR PEER REVIEW 8 of 36
2. Macrocyclic Alkaloids
2.1.1. Densanins
.
2.2.1. Njaoamines
Njaoamines are a group of biologically active alkaloids containing
a tricyclic nitrogenated nucleus with two hydrocarbon bridges, one
of which embeds an 8-hydroxyquinoline moiety. Njaoamines A–F (3–8)
(Figure 3) were isolated from the Haplosclerida sponge Reniera sp.
[13], whereas njaoamines G (9) and H (10) were isolated from the
marine sponge Neopetrosia sp. [14] and njaoamine I (11) from the
Haliclona (Reniera) sp. (Figure 3) [15]. Njaoamines showed
cytotoxic effects against NSLC A-549 (lung), HT-29 (colon), and
MDA-MB-231 (breast) human tumor cell lines. Compounds 3–8 and 11
showed cytotoxic effects, with GI50 values ranging from 1.5 to 7.2
μΜ against NSLC A-549, from 1.4 to 6.7 μΜ against HT-29, and from
1.5 to 7.2 μΜ against MDA-MB-23 [13,15]. Compounds 9 and 10
exhibited potent toxicity toward brine shrimp, with LD50 values of
0.17 and 0.08 μg/mL, respectively [14]. Compound 11 displayed
neither an inhibitory effect on human recombinant topoisomerase 1
nor inhibition of the interaction between programmed cell death
protein 1(PD-1) and its natural ligand, programmed death-ligand
1(PD-L1), even at the highest concentration tested, 100 μM
[15].
Figure 2. Structures 1 and 2.
2.2. Macrocycles Containing a Quinoline Moiety
Njaoamines
Njaoamines are a group of biologically active alkaloids containing
a tricyclic nitrogenated nucleus with two hydrocarbon bridges, one
of which embeds an 8-hydroxyquinoline moiety. Njaoamines A–F (3–8)
(Figure 3) were isolated from the Haplosclerida sponge Reniera sp.
[13], whereas njaoamines G (9) and H (10) were isolated from the
marine sponge Neopetrosia sp. [14] and njaoamine I (11) from the
Haliclona (Reniera) sp. (Figure 3) [15]. Njaoamines showed
cytotoxic effects against NSLC A-549 (lung), HT-29 (colon), and
MDA-MB-231 (breast) human tumor cell lines. Compounds 3–8 and 11
showed cytotoxic effects, with GI50 values ranging from 1.5 to 7.2
µM against NSLC A-549, from 1.4 to 6.7 µM against HT-29, and from
1.5 to 7.2 µM against MDA-MB-23 [13,15]. Compounds 9 and 10
exhibited potent toxicity toward brine shrimp, with LD50 values of
0.17 and 0.08 µg/mL, respectively [14]. Compound 11 displayed
neither an inhibitory effect on human recombinant topoisomerase 1
nor inhibition of the interaction between programmed cell death
protein 1(PD-1) and its natural ligand, programmed death-ligand
1(PD-L1), even at the highest concentration tested, 100 µM
[15].
2.3. Macrocycles Containing a Bis-Quinolizidine Moiety
Petrosins
Petrosin (12), the first reported bis-quinolizidine scaffold linked
through a C-16 ring from Petrosia seriata [16]. Later on, two
ichthyotoxic bis-quinolizidine alkaloids, petrosins A (13) and B
(14), were isolated from the same sponge [17]. In 1988, the
structure of petrosin A (13) was revised through 2D-NMR studies by
Braekman et al. [18]. Aragupetrosine A (15), along with 12 and 13,
was reported from an Okinawan marine sponge, Xestospongia sp. [19]
(Figure 4). Compound 15 consists of the
3β-methyl-trans-2-oxaquinolizidine and
3‘α-methyl-trans-1-oxoquinolizidine moieties joined by two alkyl
chains, which can be viewed as one half moiety of petrosin (12) and
the 3‘ α-methyl-trans-1-oxoquinolizidine group [19].
Mar. Drugs 2020, 18, 368 9 of 34
Mar. Drugs 2020, 18, x FOR PEER REVIEW 9 of 36
N NH2
HO
N
N
R1
R2
R3
3: R1 = OH, R2 = Me, R3 = H 4: R1 = OH, R2 = R3 = Me 5: R1 = R2 =
R3 = H 6: R1 = R3 = H, R2 = Me
N NH2
1
2.3.1. Petrosins
Petrosin (12), the first reported bis-quinolizidine scaffold linked
through a C-16 ring from Petrosia seriata [16]. Later on, two
ichthyotoxic bis-quinolizidine alkaloids, petrosins A (13) and B
(14), were isolated from the same sponge [17]. In 1988, the
structure of petrosin A (13) was revised through 2D-NMR studies by
Braekman et al. [18]. Aragupetrosine A (15), along with 12 and 13,
was reported from an Okinawan marine sponge, Xestospongia sp. [19]
(Figure 4). Compound 15 consists of the 3β-
methyl-trans-2-oxaquinolizidine and
3`α-methyl-trans-1-oxoquinolizidine moieties joined by two alkyl
chains, which can be viewed as one half moiety of petrosin (12) and
the 3 α-methyl-trans-1- oxoquinolizidine group [19].
Compounds 12 and 13, isolated from Xestospongia muta, did not show
growth inhibition against LU-1 (lung), HepG-2 (liver), HL-60
(leukemia), MCF-7 (breast), and SK-Mel-2 (melanoma) human cancer
cells [20]. However, compounds 12, 13, and 15 exhibited
vasodilative activity, and 12 and 13 were two-fold more active than
papaverine [19]. In addition to ichthyotoxic and vasodilative
activities, 12 and 13, isolated from the sponge P. similis, showed
significant in vitro antiviral activity against human
immunodeficiency virus (HIV-1), with IC50 values of 41.3 and 52.9
μM, respectively [21]. Moreover, 12 and 13 inhibited the early
replication of HIV-1 as indicated by multinuclear activation of a
galactosidase indicator (MAGI) assay, with giant cell formation and
inhibition of human immunodeficiency virus-1 reverse transcriptase
(RT) at 10.6 and 14.8 μM [21], respectively. Interestingly, 12 did
not only show higher activity against HIV than 13 but is also more
stable than 13 [21]. Xestosin A (16), another
bis-quinolizidine-containing macrocycle, was isolated from the
Papua New Guinean sponge Xestospongia exigua [22].
N
N
14
H
H
O
O
N
N
13
O
O
H
H
N
N
12
O
O
H
H
N
N
16
O
O
H
H
N
N
O
15
3 2
Figure 4. Structures of 12–16.
Figure 3. Structures of 3–11.
Mar. Drugs 2020, 18, x FOR PEER REVIEW 9 of 36
N NH2
HO
N
N
R1
R2
R3
3: R1 = OH, R2 = Me, R3 = H 4: R1 = OH, R2 = R3 = Me 5: R1 = R2 =
R3 = H 6: R1 = R3 = H, R2 = Me
N NH2
1
2.3.1. Petrosins
Petrosin (12), the first reported bis-quinolizidine scaffold linked
through a C-16 ring from Petrosia seriata [16]. Later on, two
ichthyotoxic bis-quinolizidine alkaloids, petrosins A (13) and B
(14), were isolated from the same sponge [17]. In 1988, the
structure of petrosin A (13) was revised through 2D-NMR studies by
Braekman et al. [18]. Aragupetrosine A (15), along with 12 and 13,
was reported from an Okinawan marine sponge, Xestospongia sp. [19]
(Figure 4). Compound 15 consists of the 3β-
methyl-trans-2-oxaquinolizidine and
3`α-methyl-trans-1-oxoquinolizidine moieties joined by two alkyl
chains, which can be viewed as one half moiety of petrosin (12) and
the 3 α-methyl-trans-1- oxoquinolizidine group [19].
Compounds 12 and 13, isolated from Xestospongia muta, did not show
growth inhibition against LU-1 (lung), HepG-2 (liver), HL-60
(leukemia), MCF-7 (breast), and SK-Mel-2 (melanoma) human cancer
cells [20]. However, compounds 12, 13, and 15 exhibited
vasodilative activity, and 12 and 13 were two-fold more active than
papaverine [19]. In addition to ichthyotoxic and vasodilative
activities, 12 and 13, isolated from the sponge P. similis, showed
significant in vitro antiviral activity against human
immunodeficiency virus (HIV-1), with IC50 values of 41.3 and 52.9
μM, respectively [21]. Moreover, 12 and 13 inhibited the early
replication of HIV-1 as indicated by multinuclear activation of a
galactosidase indicator (MAGI) assay, with giant cell formation and
inhibition of human immunodeficiency virus-1 reverse transcriptase
(RT) at 10.6 and 14.8 μM [21], respectively. Interestingly, 12 did
not only show higher activity against HIV than 13 but is also more
stable than 13 [21]. Xestosin A (16), another
bis-quinolizidine-containing macrocycle, was isolated from the
Papua New Guinean sponge Xestospongia exigua [22].
N
N
14
H
H
O
O
N
N
13
O
O
H
H
N
N
12
O
O
H
H
N
N
16
O
O
H
H
N
N
O
15
3 2
1
Figure 4. Structures of 12–16. Figure 4. Structures of 12–16.
Compounds 12 and 13, isolated from Xestospongia muta, did not show
growth inhibition against LU-1 (lung), HepG-2 (liver), HL-60
(leukemia), MCF-7 (breast), and SK-Mel-2 (melanoma) human cancer
cells [20]. However, compounds 12, 13, and 15 exhibited
vasodilative activity, and 12 and 13 were two-fold more active than
papaverine [19]. In addition to ichthyotoxic and vasodilative
activities, 12 and 13, isolated from the sponge P. similis, showed
significant in vitro antiviral activity against human
immunodeficiency virus (HIV-1), with IC50 values of 41.3 and 52.9
µM, respectively [21]. Moreover, 12 and 13 inhibited the early
replication of HIV-1 as indicated by multinuclear activation of a
galactosidase indicator (MAGI) assay, with giant cell formation and
inhibition of human immunodeficiency virus-1 reverse transcriptase
(RT) at 10.6 and 14.8 µM [21], respectively. Interestingly, 12 did
not only show higher activity against HIV than 13 but is also more
stable than 13 [21]. Xestosin A (16), another
bis-quinolizidine-containing macrocycle, was isolated from the
Papua New Guinean sponge Xestospongia exigua [22].
2.4. Macrocycles Containing a Bis-1-Oxaquinolizidine Moiety
Xestospongins/Araguspongines
Araguspongines (xestospongins) are a class of macrocyclic alkaloids
consisting of a 20-membered ring and two 1-oxaquinolizidine
moieties. Xestospongins A (araguspongine D) (17), B (18), C
(araguspongine E) (19), and D (araguspongine A) (20) were isolated
from the Australian sponge Xestospongia exigua and from
Xestospongia sp. [17,23], whereas xestospongins E–J (21–26) (Figure
5) were isolated from the sponge Oceanapia sp. [24]. Compounds
17–20 were found to have an in vivo vasodilator activity [17]. In
addition to this activity, 19 and 20 exhibited moderate
antimicrobial activity against Aspergillus fumigatus, Aspergillus
niger, Rhodotorula, Candida albicans, and Cryptococcus neoformans
and moderate to strong antibacterial activity toward Staphyloccus
aureus and Escherichia coli [24].
Mar. Drugs 2020, 18, 368 10 of 34
Mar. Drugs 2020, 18, x FOR PEER REVIEW 12 of 36
N
O
N
O
H
H
31
N
O
N
O
N
O
N
O
H
H
17
N
O
N
O
21
HO
OH
N
O
N
O
22
HO
OH
O
N
O
N
O
23
HO
OH
O
O
N
O
N
O
24: R1 = R2 = H 25: R1 = H, R2 = OH 26: R1 = R2 = OH
R1
R2
27
N
O
N
O
H
H
HO
N
O
N
O
H
H
N
O
N
O
H
H
R
R
N
O
N
O
H
H
R1
R2
33: R1 = -Me, R2 = H 34: R1 = -Me, R2 = H 35: R1 = -Me, R2 = -Me
36: R1 = -Me, R2 = -Me
N
O
N
O
H
H
38
HO
9a9 2
2` 9`9a`
Figure 5. Structures of 17–44. Figure 5. Structures of 17–44.
(+)-7S-Hydroxyxestospongin A (27) [25], demethylxestospongin B (28)
[26], and C (29) were isolated from Xestospongia sp. [27]. Compound
28 was also isolated from Neopetrosia exigua, along with a
quinolizidine derivative, 9′-epi-3β,3′β–dimethylxestospongin C (30)
[28]. Compounds 28–30 showed cytotoxic activity with ED50 values of
0.8, 2.0, and 0.2 µg/mL against L1210 (mouse lymphocytic leukemia)
and ED50 values of 2.5, 2.5, and 2.0 µg/mL against KB (human
epidermoid carcinoma) cells, respectively [26].
Mar. Drugs 2020, 18, 368 11 of 34
Araguspongines B (31), C (32), F–H (33–35), and J (36) (Figure 5)
were isolated from the Okinawan sponge Xestospongia sp. [29]. A
bis-1-quinolizidine derivative, 3α-methylaraguspongine (37), along
with 17, 19, 20, and 32, were isolated from Xestospongia exigua
[30].
On the basis of molecular modeling and NMR spectroscopy, Hoye et
al. re-examined the chemical structures of several members of
araguspongine/xestospongin families of alkaloids [31]. They studied
the cis- vs. trans-decalin-like conformers and the relative
configuration of various substituted 1-oxaquinolizidine-containing
macrocycles. They found that (i) for the unsubstituted parent
compound 1-oxaquinolizidine, the trans-decalin-like isomer is the
dominant contributor based on 1HNMR studies (up-field chemical
shift value for the N-CH-O proton (δ 3.41), consistent with two
sets of anti-periplanar non-bonding electrons to C9-Ha9, along with
coupling constant values (J), fit the dihedral angle of trans-like
isomer), and (ii) trans-dialkylated ring substitutions are largely
common in the trans-decalin-like conformation, while
trans-dialkylated ring substitutions are largely common in the
trans-decalin-like conformation, and dialkylated ring substitutions
are largely common in the cis-decalin-like conformation [31]. The
thermodynamic stability of these conformations was due to the
trans-dialkylated orientation and the presence of a
cis-decalin-like structure, which provide more stability by their
anomeric effect [32].
In 2002, two new N-oxide araguspongines, araguspongines K (38) and
L (39), along with 17, were isolated from the Red Sea sponge
Xestospongia exigua [33]. Both 38 and 39 exhibited cytotoxicity
against HL-60 cells with an IC50 value of 5.5 µM, whereas 17 showed
an IC50 value of 5.9 µM [33]. Later on, Liu et al. isolated
araguspongine M (40), along with 17 and 31, from the same sponge
[34].
Three compounds, identified as LT-9 (41), LT-10 (42), and LT-6 (43)
(Figure 5), were isolated from the Thai water sponge Xestospongia
sp.; however, their structures were clarified and renamed as
araguspongines N−P (41–43) [20,35]. Araguspongines A, B, C, F, G,
H, and J (20, 31, 32, 33, 34, 35, and 36) and M–P (40–43) possess
bis-1-oxaquinolizidine moiety, whereas 38 and 39 have a
bis-1-oxaquinolizidine N-oxide moiety [17,33]. The biological
activities of araguspongines include antifouling, cytotoxic,
antitubercular, antimalarial, somatostatin, and vasoactive
intestinal peptide inhibitory effects [33,36].
Dung et al. reported the isolation of meso-araguspongine C (44)
from the sponge Xestospongia muta. Compounds 32 and 44 showed
significant cytotoxic activity against LU-1, HepG-2, HL-60, MCF-7,
and SK-Mel-2 human cancer cells, with IC50 values ranging from 0.43
to 1.02 µM; however, 44 is more potent than 32 [20]. Compounds 20,
32, 38, and 39 exhibited cytotoxicity against breast cancer BT-474
cells, with IC50 values of 9.3, 15.2, 29.5, and 35.6 µM,
respectively [37].
Araguspongines show significant antifouling activity with low
toxicity against both micro- and macrofouling organisms [33,36].
Their potent antibacterial activity has been shown against seven
strains of fouling bacteria i.e., Pseudomonas aeruginosa,
Pseudomonas putida, Pseudomonas chlororaphis, Pseudoalteromonas
haloplanktis, Bacillus cereus, Bacillus pumilus, and Bacillus
megaterium by a fraction of bis-1-oxaquinolizidine alkaloids
[36].
Araguspongines that possess a macrocyclic ring with two cis- or
trans-dialkylated orientations at C-2 and C-9 on both
l-oxaquinolizidine rings, as well as two trans- or cis-decalin-like
rings, showed potent biological activities. For example 31, 32, 33,
40, and 44 exhibited growth-inhibitory activity against HL-60, with
IC50 values ranging from 0.62 to 5.90 µg/mL. On the contrary,
compounds that have both cis- and trans-dialkylated orientation and
one cis-decalin-like ring, or those that possess
bis-1-oxaquinolizidine N-oxide, showed weak or no activity. This
was demonstrated by the fact that 19, 20, and 39 exhibited weak or
no biological activity against HL-60 cells, with IC50 values
ranging from 16.79 to 22.95 µg/mL [20]. Compound 27 was inactive
against foulant organisms [25]. Therefore, the stability of the
aforementioned araguspongines’ conformation seems to influence
their biological activity.
Compounds 19 and 20, containing one trans- and one cis-decalin-like
ring, exhibited weaker activity against HL-60 when compared to
other araguspongines [26]. Compound 20 showed moderate
Mar. Drugs 2020, 18, 368 12 of 34
activity relative to 18 and 28 against KB and L1210 cells. This
effect might be due to the presence of the OH group at C-2 in 20
[26].
Compound 18 displaced [3H]IP3 from the membranes of cerebellar and
skeletal myotube homogenates, with EC50 values of 44.6 ± 1.1 µM and
27.4 ± 1.1 µM, respectively [38]. This compound inhibited
bradykinin-induced Ca2+ signals of the neuroblastoma cells
(NG108-15) and selectively blocks the slow intracellular Ca2+
signal induced by membrane depolarization with high external K+ (47
mM) in rat skeletal myotubes [38]. Compound 18 decreases
IP3-induced Ca2+ oscillations, with an EC50 value of 18.9 ± 1.35 µM
[38]. Conclusively, 18 showed cell-permeant activity and was a
competitive inhibitor of IP3 receptors in cultured rat myotubes,
and it separated myonuclei and NG108-15 cells [38].
The organic extract Haliclona exigua exhibited adulticidal and
embryostatic actions against human lymphatic filarial parasite B.
malayi in an experimental rodent model, and this activity could be
due to the presence of araguspongin C [4]. Compound 32 showed
potent activity against the Mycobacterium tuberculosis strain
H37Rv, with a minimum inhibitory concentration (MIC) value of 3.94
µM (positive control: rifampin, IC50 = 0.61 µM) [33].
Compound 32 displayed an in vitro anti-proliferative effect against
multiple breast cancer cell lines in a dose-dependent manner. It
causes the induction of autophagic cell death in
HER2-overexpressing BT-474 breast cancer cells, which was
characterized by vacuole formation and upregulation of autophagy
markers. It displayed autophagy associated with the inhibition of
c-Met and HER2 receptor tyrosine kinase activation. Compound 32
also suppressed the depression of the PI3K/Akt/mTOR signaling
cascade in the breast cancer cells that undertake autophagy. The
induction of autophagic death in BT-474 cells was associated with
reduced levels of the inositol 1,4,5-trisphosphate receptor upon
management with an effective concentration of 32 [37].
2.5. Macrocycles Containing a 3-Alkylpiperidine Moiety
2.5.1. Pentacyclic Derivatives
Saraines/Sarains
An investigation of the marine sponge Reniera sarai led to the
identification of saraines 1–3 (45–47) [39], which belong to the
3-alkylpiperidine subclass (Figure 6). The complexity of their
structures delayed a complete elucidation until the
mid-1980s.
The main scaffold of saraines consists of a tetrahydropyridine
moiety attached to a trans-2-oxoquinolizidine ring system. They
possess a pentacyclic skeleton that includes a trisubstituted
alkene and a carbonyl group. The two cycles are supplied by linking
the two heterocyclic systems with linear alkyl chains [39]. The
three stereoisomers of saraines 1–3 have been reported and
identified as isosaraines 1–3 (48–50) [40–42], which were also
isolated from R. sarai as minor components. Saraines A–C (51–53)
were isolated from the Mediterranean sponge R. sarai and possess an
entirely different structure from those of the previously reported
saraines 1–3 (45–47) and isosaraines 1–3 (48–50). The entire
skeleton of 51–53 is composed of two piperidine rings condensed to
form a central nucleus, which linked to a pair of alkyl chains
[43,44]. Compounds 45–47 and 51–53 (Figure 6) exhibited
antibacterial activity against S. aureus with MIC values between
6.25 and 50 µg/mL; a lethality against Aspergillus salina, with
LD50 values between 2.5 and 46.7 µg/mL; an inhibitory effect
against potato disc infected with Aspergillus tumefaciens, with
inhibition percentages between 16% and 55%; and inhibition of the
development of fertilized sea urchin eggs, with IC50 values between
1.56 and 6.25 µg/mL. However, 45 showed neither antimicrobial
activity nor the inhibition of development of fertilized sea urchin
eggs at a concentration as high as 50 µg/mL [45]. Overall, saraines
show an increase in biological activity with an increase in the
size of the macrocyclic ring (A) within the two groups from 45 to
47 and from 51 to 53 (Figure 6).
Mar. Drugs 2020, 18, 368 13 of 34
Mar. Drugs 2020, 18, x FOR PEER REVIEW 13 of 36
2.5. Macrocycles Containing a 3-Alkylpiperidine Moiety
2.5.1. Pentacyclic Derivatives
Saraines/Sarains
An investigation of the marine sponge Reniera sarai led to the
identification of saraines 1–3 (45– 47) [39], which belong to the
3-alkylpiperidine subclass (Figure 6). The complexity of their
structures delayed a complete elucidation until the
mid-1980s.
Figure 6. Structures of 45–53.
The main scaffold of saraines consists of a tetrahydropyridine
moiety attached to a trans-2- oxoquinolizidine ring system. They
possess a pentacyclic skeleton that includes a trisubstituted
alkene and a carbonyl group. The two cycles are supplied by linking
the two heterocyclic systems with linear alkyl chains [39]. The
three stereoisomers of saraines 1–3 have been reported and
identified as isosaraines 1–3 (48–50) [40–42], which were also
isolated from R. sarai as minor components. Saraines A–C (51–53)
were isolated from the Mediterranean sponge R. sarai and possess an
entirely different structure from those of the previously reported
saraines 1–3 (45–47) and isosaraines 1–3 (48–50). The entire
skeleton of 51–53 is composed of two piperidine rings condensed to
form a central nucleus, which linked to a pair of alkyl chains
[43,44]. Compounds 45–47 and 51–53 (Figure 6) exhibited
antibacterial activity against S. aureus with MIC values between
6.25 and 50 μg/mL; a lethality against Aspergillus salina, with
LD50 values between 2.5 and 46.7 μg/mL; an inhibitory effect
against potato disc infected with Aspergillus tumefaciens, with
inhibition percentages between 16% and 55%; and inhibition of the
development of fertilized sea urchin eggs, with IC50 values between
1.56 and 6.25 μg/mL. However, 45 showed neither antimicrobial
activity nor the inhibition of development of fertilized sea urchin
eggs at a concentration as high as 50 μg/mL [45]. Overall, saraines
show an increase in biological activity with an increase in the
size of the macrocyclic ring (A) within the two groups from 45 to
47 and from 51 to 53 (Figure 6).
Figure 6. Structures of 45–53.
Madangamines
Madangamines A (54) [46] and B–E (55–58) [47] were isolated from
the marine sponge X. ingens, whereas madangamine F (59) was
isolated from the sponge Pachychalina alcaloidifera [48]. Because
of their diazatricyclic skeleton and two peripheral macrocyclic
rings, madangamines have an unusual chemical structure. The
macrocyclic ring D in madangamines varies in size, ranging from 13
to 15 carbon atoms. The ring E in 54–58 is an 11-membered ring with
two double bonds, whereas 59 possesses a 13-membered ring with four
double bonds [49] (Figure 7).
Mar. Drugs 2020, 18, x FOR PEER REVIEW 14 of 36
Madangamines
Madangamines A (54) [46] and B–E (55–58) [47] were isolated from
the marine sponge X. ingens, whereas madangamine F (59) was
isolated from the sponge Pachychalina alcaloidifera [48]. Because
of their diazatricyclic skeleton and two peripheral macrocyclic
rings, madangamines have an unusual chemical structure. The
macrocyclic ring D in madangamines varies in size, ranging from 13
to 15 carbon atoms. The ring E in 54–58 is an 11-membered ring with
two double bonds, whereas 59 possesses a 13-membered ring with four
double bonds [49] (Figure 7).
Compound 54 displayed significant in vitro cytotoxicity toward
murine leukemia P388 (ED50 value of 0.93 μg/mL), lung A549 (ED50
value of 14 μg/mL), MCF-7 (ED50 value of 5.7 μg/mL), and brain U373
(ED50 value of 5.1 μg/mL) cancer cell lines, respectively [46].
Compound 59 showed weak cytotoxicity, with EC50 values of 16.7,
19.8, >25, and 16.2 μg/mL against HL-60, SF 295 (human CNS),
HCT-8 (colon), and MDA-MB435 (melanoma) cancer cell lines,
respectively [48].
54
N
N
56
N
N
57
N
N
55
N
N
58
Haliclonadiamines
The bis-indane macrocycles (10E,12Z)-haliclonadiamine (60) and
(10Z,12E)-haliclonadiamine (61) were isolated from Halichondria
panicea [50], whereas papuamine (62) [51] and haliclonadiamine (63)
[52] were isolated from Haliclona sp. Compounds 60–63 showed a
potent effect against Mycobacterium smegmatis with inhibitory zones
of 7–16 mm at a concentration of 10 μg/disc [53]. Compound 63
exhibited a potent effect with an inhibition zone of 16 mm at 10
μg/disc. SAR analysis suggests that the antitubercular activity of
these compounds favors the 13-membered ring E and the 10E,12E
configuration [53] (Figure 8). Recently, Liu et al. have revised
the structure of 63 using X-ray crystallography, establishing the
absolute configurations of the stereogenic carbons as
1S,3R,8S,9R,15S,20R,22R (64), which are opposite to those
previously reported for 63 [54].
NH HN
Compound 54 displayed significant in vitro cytotoxicity toward
murine leukemia P388 (ED50
value of 0.93 µg/mL), lung A549 (ED50 value of 14 µg/mL), MCF-7
(ED50 value of 5.7 µg/mL), and brain U373 (ED50 value of 5.1 µg/mL)
cancer cell lines, respectively [46]. Compound 59 showed weak
cytotoxicity, with EC50 values of 16.7, 19.8, >25, and 16.2
µg/mL against HL-60, SF 295 (human CNS), HCT-8 (colon), and
MDA-MB435 (melanoma) cancer cell lines, respectively [48].
Mar. Drugs 2020, 18, 368 14 of 34
Haliclonadiamines
The bis-indane macrocycles (10E,12Z)-haliclonadiamine (60) and
(10Z,12E)-haliclonadiamine (61) were isolated from Halichondria
panicea [50], whereas papuamine (62) [51] and haliclonadiamine (63)
[52] were isolated from Haliclona sp. Compounds 60–63 showed a
potent effect against Mycobacterium smegmatis with inhibitory zones
of 7–16 mm at a concentration of 10 µg/disc [53]. Compound 63
exhibited a potent effect with an inhibition zone of 16 mm at 10
µg/disc. SAR analysis suggests that the antitubercular activity of
these compounds favors the 13-membered ring E and the 10E,12E
configuration [53] (Figure 8). Recently, Liu et al. have revised
the structure of 63 using X-ray crystallography, establishing the
absolute configurations of the stereogenic carbons as
1S,3R,8S,9R,15S,20R,22R (64), which are opposite to those
previously reported for 63 [54].
Mar. Drugs 2020, 18, x FOR PEER REVIEW 14 of 36
Madangamines
Madangamines A (54) [46] and B–E (55–58) [47] were isolated from
the marine sponge X. ingens, whereas madangamine F (59) was
isolated from the sponge Pachychalina alcaloidifera [48]. Because
of their diazatricyclic skeleton and two peripheral macrocyclic
rings, madangamines have an unusual chemical structure. The
macrocyclic ring D in madangamines varies in size, ranging from 13
to 15 carbon atoms. The ring E in 54–58 is an 11-membered ring with
two double bonds, whereas 59 possesses a 13-membered ring with four
double bonds [49] (Figure 7).
Compound 54 displayed significant in vitro cytotoxicity toward
murine leukemia P388 (ED50 value of 0.93 μg/mL), lung A549 (ED50
value of 14 μg/mL), MCF-7 (ED50 value of 5.7 μg/mL), and brain U373
(ED50 value of 5.1 μg/mL) cancer cell lines, respectively [46].
Compound 59 showed weak cytotoxicity, with EC50 values of 16.7,
19.8, >25, and 16.2 μg/mL against HL-60, SF 295 (human CNS),
HCT-8 (colon), and MDA-MB435 (melanoma) cancer cell lines,
respectively [48].
54
N
N
56
N
N
57
N
N
55
N
N
58
Haliclonadiamines
The bis-indane macrocycles (10E,12Z)-haliclonadiamine (60) and
(10Z,12E)-haliclonadiamine (61) were isolated from Halichondria
panicea [50], whereas papuamine (62) [51] and haliclonadiamine (63)
[52] were isolated from Haliclona sp. Compounds 60–63 showed a
potent effect against Mycobacterium smegmatis with inhibitory zones
of 7–16 mm at a concentration of 10 μg/disc [53]. Compound 63
exhibited a potent effect with an inhibition zone of 16 mm at 10
μg/disc. SAR analysis suggests that the antitubercular activity of
these compounds favors the 13-membered ring E and the 10E,12E
configuration [53] (Figure 8). Recently, Liu et al. have revised
the structure of 63 using X-ray crystallography, establishing the
absolute configurations of the stereogenic carbons as
1S,3R,8S,9R,15S,20R,22R (64), which are opposite to those
previously reported for 63 [54].
NH HN
17
19
21
25
15
Figure 8. Structures of 60–64. Figure 8. Structures of 60–64.
Ingenamines and Ingamines
Ingamines A (65) and B (66) [55], ingenamine A (67) [56], and
ingenamines B–F (68–72) [57] were all isolated from X. ingens,
whereas ingenamine G (73) was isolated from the sponge Pachychalina
sp. [8]. Meanwhile, dihydroingenamine D (74) and
22(S)-hydroxyingamine A (75) were isolated from the sponge Petrosid
Ng5 Sp5 [58] (Figure 9). Compounds 63, 74, and 75 exhibited
antiplasmodial activity against chloroquine-resistant (W2) and
chloroquine-sensitive (D6) strains of Plasmodium falciparum, with
IC50 values of 57 and 72 ng/mL for 63, 78 and 90 ng/mL for 74, and
140 and 200 ng/mL for 75, respectively [58]. Compound 73 exhibited
cytotoxic activity, with IC50 values of 11.3, 9.8, and 8.6 µg/mL
against MCF-7, B16 (leukemia), and HCT-8 cancer cells, respectively
[8]. Moreover, this compound showed antimicrobial activity with MIC
values at 8 µg/mL against M. tuberculosis H37Rv, 105 µg/mL against
S. aureus (ATCC 25923), 75 µg/mL against E. coli (ATCC 25922), and
with MIC values ranging from 10 to 50 µg/mL against two of four
strains of oxacillin-resistant S. aureus [8]. Xestocyclamine (76)
is a pseudo-enantiomeric to 67, and they differ only in the
location of the carbon–carbon double bond in the 11-membered ring.
Compound 76 exhibited moderate inhibitory activity against protein
kinase C, with an IC50 value of 4 µg/mL. Interestingly, 76 showed
selectivity against IL-1 (interleukin), as it showed no activity
against other cancer-relevant targets [59].
Mar. Drugs 2020, 18, 368 15 of 34
Mar. Drugs 2020, 18, x FOR PEER REVIEW 15 of 36
Ingenamines and Ingamines
Ingamines A (65) and B (66) [55], ingenamine A (67) [56], and
ingenamines B–F (68–72) [57] were all isolated from X. ingens,
whereas ingenamine G (73) was isolated from the sponge Pachychalina
sp. [8]. Meanwhile, dihydroingenamine D (74) and
22(S)-hydroxyingamine A (75) were isolated from the sponge Petrosid
Ng5 Sp5 [58] (Figure 9). Compounds 63, 74, and 75 exhibited
antiplasmodial activity against chloroquine-resistant (W2) and
chloroquine-sensitive (D6) strains of Plasmodium falciparum, with
IC50 values of 57 and 72 ng/mL for 63, 78 and 90 ng/mL for 74, and
140 and 200 ng/mL for 75, respectively [58]. Compound 73 exhibited
cytotoxic activity, with IC50 values of 11.3, 9.8, and 8.6 μg/mL
against MCF-7, B16 (leukemia), and HCT-8 cancer cells, respectively
[8]. Moreover, this compound showed antimicrobial activity with MIC
values at 8 μg/mL against M. tuberculosis H37Rv, 105 μg/mL against
S. aureus (ATCC 25923), 75 μg/mL against E. coli (ATCC 25922), and
with MIC values ranging from 10 to 50 μg/mL against two of four
strains of oxacillin-resistant S. aureus [8]. Xestocyclamine (76)
is a pseudo-enantiomeric to 67, and they differ only in the
location of the carbon– carbon double bond in the 11-membered ring.
Compound 76 exhibited moderate inhibitory activity against protein
kinase C, with an IC50 value of 4 μg/mL. Interestingly, 76 showed
selectivity against IL-1 (interleukin), as it showed no activity
against other cancer-relevant targets [59].
N
N
R2
R3
R1
18
17
N
N
R
N
N
OH
2.5.2. Tetracyclic Derivatives
Halicyclamines A (77) and (-) halicyclamine B (78) were isolated
from Haliclona sp. [60] and Xestospongia sp. [61], respectively
(Figure 10). Haliclonacyclamines A (79) and B (80) [62] were
isolated from Haliclona sp. 22-Hydroxyhaliclonacyclamine B (81)
[63], 2-epi-tetradehydro haliclonacyclamine (82),
tetradehydrohaliclonacyclamine A mono-N-oxide (83), and
tetradehydrohaliclonacyclamine A (84) were isolated from
Halichondria sp. [64]. The anti-dormant mycobacterial activity of
77 was reported by Kobayashi et al., with the correlation of Ded A
Protein to the mechanism of action of 77 under dormancy-inducing
hypoxic and standard aerobic growth conditions [65]. Compound 78
showed weak and selective antimicrobial activity and also
exhibited
Figure 9. Structures of 65–76.
2.5.2. Tetracyclic Derivatives
Halicyclamines
Halicyclamines A (77) and (-) halicyclamine B (78) were isolated
from Haliclona sp. [60] and Xestospongia sp. [61], respectively
(Figure 10). Haliclonacyclamines A (79) and B (80) [62] were
isolated from Haliclona sp. 22-Hydroxyhaliclonacyclamine B (81)
[63], 2-epi-tetradehydro haliclonacyclamine (82),
tetradehydrohaliclonacyclamine A mono-N-oxide (83), and
tetradehydrohaliclonacyclamine A (84) were isolated from
Halichondria sp. [64]. The anti-dormant mycobacterial activity of
77 was reported by Kobayashi et al., with the correlation of Ded A
Protein to the mechanism of action of 77 under dormancy-inducing
hypoxic and standard aerobic growth conditions [65]. Compound 78
showed weak and selective antimicrobial activity and also exhibited
growth inhibitions of 50% and 20% at 200 µg/disk against Bacillus
subtilis and E. coli, respectively, but showed no activity toward
C. albicans [61]. Compound 79, isolated from the Haliclona sponge
of the Solomon Islands, exhibited a great antiplasmodial effect in
vivo and in vitro against Plasmodium vinckei petteri-infected mice
and the chloroquine-resistant P. falciparum strain FCB1. It also
shows IC50 values of 0.052 and 0.33 µg/mL against the P. falciparum
strain FCB1 and chloroquine-sensitive 3D7, respectively [66]. In
vitro, 79 displayed cytotoxicity against MCF-7 cells (2.6 µg/mL)
[66].
Haliclonacyclamines C (85) and D (86) were isolated from a specimen
of Haliclona sp. collected from Heron Island on the Great Barrier
Reef [67].
Haliclonacyclamine E (87) was isolated from the Haplosclerida
sponge Arenosclera brasiliensis, which is endemic to the
Southeastern coast of Brazil [68]. Compound 87 displayed
cytotoxicity against HL60, B16, L929 (brosarcoma), and U-138
(colon) cancer cell lines, with IC50 values of 4.23, 1.82, 3.89,
and 6.06 µg/mL, respectively [69]. Haliclonacyclamine F (88) was
isolated from the sponge P. alcaloidifera. Compound 88 exhibited
cytotoxicity against HL-60, SF 295, HCT-8, and MDA-MB435 cancer
cell lines with IC50 values of 2.2, 4.5, 8.6, and 1.0 µg/mL,
respectively [48]. Halichondramine (89) was isolated from the Red
Sea sponge Halichondria sp. [70].
A bis-piperidine alkaloid, neopetrosiamine A (90), isolated from
Neopetrosia proxima, showed potent inhibitory activity against
MCF-7, CCRF-CEM (leukemia), and MALME-3M melanoma cancer cells,
with IC50 values of 3.5, 2.0, and 1.5 µM, respectively. Compound 90
also exhibited in vitro
Mar. Drugs 2020, 18, 368 16 of 34
cytotoxicity, with an MIC value of 7.5 µg/mL, toward a pathogenic
strain of M. tuberculosis (H37Rv) in a microplate Alamar Blue assay
(MABA). Additionally, 90 showed antiplasmodial activity against P.
falciparum, with an IC50 value of 2.3 µM [71]. Although 78 and 90
have very similar structural features, with one of the alkyl chains
of 90 being shorter than that of 78 and exhibiting stronger
activity against P. falciparum than 78, 78 showed higher activity
than 90 against MCF7 breast cancer cells [71].
Tetradehydrohalicyclamine B (91) and 78 were isolated from the
sponge Acanthostrongylophora ingens. Both compounds showed
inhibition against the constitutive proteasome and
immunoproteasome. Compound 78 revealed 4- to 10-fold higher
inhibitory activity than 91 [72].
Mar. Drugs 2020, 18, x FOR PEER REVIEW 16 of 36
growth inhibitions of 50% and 20% at 200 μg/disk against Bacillus
subtilis and E. coli, respectively, but showed no activity toward
C. albicans [61]. Compound 79, isolated from the Haliclona sponge
of the Solomon Islands, exhibited a great antiplasmodial effect in
vivo and in vitro against Plasmodium vinckei petteri-infected mice
and the chloroquine-resistant P. falciparum strain FCB1. It also
shows IC50 values of 0.052 and 0.33 μg/mL against the P. falciparum
strain FCB1 and chloroquine-sensitive 3D7, respectively [66]. In
vitro, 79 displayed cytotoxicity against MCF-7 cells (2.6 μg/mL)
[66].
Haliclonacyclamines C (85) and D (86) were isolated from a specimen
of Haliclona sp. collected from Heron Island on the Great Barrier
Reef [67].
N N
H H
H H
N N
H H
H H
27 28
N N
H H
H H
H
83
Figure 10. Structures of 77–96.
Haliclonacyclamine E (87) was isolated from the Haplosclerida
sponge Arenosclera brasiliensis, which is endemic to the
Southeastern coast of Brazil [68]. Compound 87 displayed
cytotoxicity against HL60, B16, L929 (brosarcoma), and U-138
(colon) cancer cell lines, with IC50 values of 4.23, 1.82, 3.89,
and 6.06 μg/mL, respectively [69]. Haliclonacyclamine F (88) was
isolated from the sponge P. alcaloidifera. Compound 88 exhibited
cytotoxicity against HL-60, SF 295, HCT-8, and MDA-MB435 cancer
cell lines with IC50 values of 2.2, 4.5, 8.6, and 1.0 μg/mL,
respectively [48]. Halichondramine (89) was isolated from the Red
Sea sponge Halichondria sp. [70].
A bis-piperidine alkaloid, neopetrosiamine A (90), isolated from
Neopetrosia proxima, showed potent inhibitory activity against
MCF-7, CCRF-CEM (leukemia), and MALME-3M melanoma cancer cells,
with IC50 values of 3.5, 2.0, and 1.5 μΜ, respectively. Compound 90
also exhibited in vitro
Figure 10. Structures of 77–96.
Arenosclerins
Arenosclerins A–C (92–94) were isolated from the Brazilian endemic
Haplosclerida sponge, A. brasiliensis [68], whereas arenosclerins D
(95) and E (96) (Figure 10) were isolated from the sponge P.
alcaloidifera [48]. Although these compounds were inactive against
C. albicans, 92 and 94 showed antibacterial activity against a
larger number of bacteria strains than 93; however, potent
antibacterial activity was exhibited by both 93 and 94. Moreover,
these compounds showed potent toxicity toward HL-60, B16, L929, and
U-138 cancer cell lines [69]. The IC50 values of 92 were 1.77,
2.34, 4.31, and 3.83 µg/mL; of 93 were 1.76, 2.24, 4.07, and 3.62
µg/mL; and of 94 were 1.71, 2.17, 3.65, and 3.60 µg/mL against B16,
L929, HL-60, and U-138 cancer cell lines, respectively [69].
Compounds 95 and 96 were tested for their cytotoxicity against
HL-60, SF 295, HCT-8, and MDA-MB-435 cancer cell lines, and their
IC50 values were 2.1, 5.9, 6.2, and 1.2 µg/mL and 6.9, 8.7, >25,
and 3.1 µg/mL, respectively [48].
Mar. Drugs 2020, 18, 368 17 of 34
2.6. Manzamines
2.6.1. Pentacyclic Manzamines
Pentacyclic manzamines are a group of macrocyclic alkaloids
containing a β-carboline moiety attached to pentacyclic rings with
a double bond between C-10 and C-11 in the eight-membered ring
[73,74].
Manzamine A hydrochloride salt (97), the first reported member of
manzamines, was isolated from Haliclona sp. [75]. This compound was
also isolated from Pellina sp. and was named keramamine A [76].
Compound 97 showed a broad spectrum of biological effects, i.e.,
potent antipathogenic activity against Leishmania donovani,
antimycobacterial activity [77], cytotoxicity against pancreatic
cancer (by inhibiting autophagy) [78], P388 [75], human colorectal
carcinoma [79], and anti-Alzheimer activity [80]. It also exhibited
an inhibitory effect against herpes simplex virus (HSV-1) [81] and
HSV-2 [82], human immunodeficiency virus (HIV) [77], as well as the
rodent malaria parasite Plasmodium berghei in vivo [10].
8-Hydroxymanzamine A (98, also known as manzamine G or manzamine K)
was isolated from Pachypellina sp. and the stereochemistry of 98
was the same as 97 (Figure 11), as both of them were
dextrorotatory. Compounds 97 and 98 exhibited moderate antitumor
activity against KB and LoVo (colon) cancer cell lines and
anti-HSV-II (herpes simplex) activity [82]. Compounds 97 and 98
displayed in vitro and in vivo antimalarial effects against P.
berghei. The percentage of the asexual erythrocytic stages
suppression, which registered after a single intraperitoneal
injection of 97 and 98 administered to infected mice, was 90%.
These compounds increased the time of living of the infected mice
to more than 240 h, using just one dose of 97 (50 mM/kg) and 98
(100 mM/kg) [83].
3,4-Dihydromanzamine A (99) and 6-hydroxymanzamine A (manzamine Y)
(100), isolated from a marine sponge Amphimpdon sp., showed
antibacterial activity against a Gram-positive bacterium, Sarcina
lutea (MIC values of 4 and 1.25 µg/mL, respectively). These
compounds also exhibited in vitro cytotoxicity against L1210 (IC50
values of 0.48 and 1.5 µg/mL, respectively) and KB cells (IC50
values of 0.61 and 2.5 µg/mL, respectively) [84].
1,2,3,4-Tetrahydro-8-hydroxymanzamine A (8-hydroxymanzamine D)
(101), and 1,2,3,4-tetrahydro- 2-N-methyl-8-hydroxymanzamine A
(8-hydroxy-2-N-methylmanzamine D) (102) (Figure 11) were isolated
from the marine sponges of the genera Petrosia and Cribochalina
[85]. Compound 102 is cytotoxic toward P388 cell line, with an ED50
value of 0.8µg/mL [85]. Manzamine D (1,2,3,4-tetrahydromanzamine A)
(103) was isolated from Ircinia sp. [86], whereas
3,4-dihydro-6-hydroxymanzamine A (104) and manzamine M (105) were
isolated from Amphimedon sp. [87]. Compound 105 was the first
reported manzamine congener with a hydroxyl group on the C13-C20
chain. Compounds 104 and 105 showed cytotoxicity against L1210
cells (IC50 values of 0.3 and 1.4 µg/mL, respectively). Moreover,
104 and 105 exhibited antibacterial activity against Sarcina lutea
(MIC values of 6.3 and 2.3 µg/mL, respectively) and Corynebacterium
xerosis (MIC values of 3.1 and 5.7 µg/mL, respectively) [87].
Bioassay-directed fractionation of the CH2Cl2 crude extract of the
Palaun sponge, employing an assay for the inhibitors of methionine
aminopeptidase-2 (Met AP-2), led to the identification of
N-methyl-epi-manzamine D (106) and epi-manzamine D (107) [88].
Neither of these compounds exhibited selectivity in the yeast assay
for inhibitors of Met AP-2; however, both compounds showed
cytotoxicity against HeLa and B16F10 melanoma cells. Compound 106
showed strong activity against the B16F10 cell line [88].
12,34-Oxamanzamine A (108) was isolated from an Indo-Pacific sponge
identified as 011ND 51 [89]. This compound possesses an unusual
ring system due to the presence of an ether bridge formed between
C-12 and C-34 of the typical manzamine structure. Compound 108
displayed less activity against malaria and the AIDS OI pathogen,
M. tuberculosis, compared to the other co-isolated manzamines,
which might be attributed to the presence of the C12–C34 ether
bridge in 108 [89] (Figure 11). ent-8-Hydroxymanzamine A (109) was
isolated from an undescribed genus of an Indo-Pacific sponge. It
exhibited improved activity against P-388, with an IC50 value of
0.25 µg/mL [90]. Compound 109 displayed in vitro growth inhibitory
effect against Trypanosoma gondii and host cell with 71%
Mar. Drugs 2020, 18, 368 18 of 34
and 38% inhibition, respectively, at a concentration of 1 µM [90].
12,28-Oxamanzamine A (110) and 12,28-oxa-8-hydroxymanzamine A (111)
were isolated from two collections of an Indo-Pacific sponge. These
compounds contain a novel manzamine-type ring system, generated
through a new ether bridge formed between C-12 and C-28 or between
C-12 and C-34 of the typical manzamine structure. These compounds
exhibited potent anti-inflammatory, antifungal, and anti-HIV-1
activities [91].
Mar. Drugs 2020, 18, x FOR PEER REVIEW 19 of 36
Figure 11. Structures of 97–113.
Acanthomanzamines A (114) and B (115), isolated from A. ingens,
contain a tetrahydroisoquinoline ring system instead of
β-carboline. Compounds 114 and 115 showed potent cytotoxicity
against HeLa cells, with IC50 values of 4.2 and 5.7 μM,
respectively. Interestingly, 114 and 115 (Figure 12) exhibited
stronger cytotoxicity against HeLa cancer cell line, but less
potent proteasome inhibitory activity than their co-isolated
β-carboline-containing manzamines, acanthomanzamines D and E [93].
Several other examples of β-carboline-based manzamines were also
reported from different sponge species. Examples of these are
pre-neo-kauluamine (116) from A. ingens [94], zamamidine C (117)
[95], zamamidine D (118) [96], nakadomarin A (119) from Amphimedon
sp. [97], ircinol A (120) from Amphimedon sp. [98], ircinal A (121)
from Ircinia sp. [86], ircinal E (122) from A. ingens [99], and
12,28-oxaircinal A (123) from Acanthostrongylophora sp. [100]. The
reported biological activities of the aforementioned compounds were
quite interesting, Compound 116 showed proteasome inhibitory
activity [94], whereas 117 displayed potent antitrypanosomal effect
against Trypanosoma brucei brucei and antimalarial activity against
P. falciparum [95]. Compound 118 exhibited antimicrobial activity
against several strains of fungi and bacteria [96], whereas 119
exhibited antimicrobial effects against C. xerosis and Trichophyton
mentagrophytes, with MIC values of 11 and 23 μg/mL, respectively
[97]. Compound 120 inhibited endothelin-converting enzyme, with an
IC50 of 55 μg/mL [98]. Compound 121 displayed cytotoxicity against
L1210 and KB cancer cells with IC50 values of 1.4 and 4.8 μg/mL,
respectively [86]. Compound 122 showed weak cytotoxicity and L5178Y
(murine lymphoma) cells with an IC50 value of 21.7 μg/mL,
respectively [99]. Pentacyclic manzamines having a ketonic group in
their eight-membered ring
Figure 11. Structures of 97–113.
Manzamine A N-oxide (112) and 3,4-dihydromanzamine A N-oxide (113)
were isolated from the Indonesian marine sponge Xestospongia
ashmorica [92]. Compound 112 showed potent cytotoxicity against
L5178Y mouse lymphoma cells with an ED50 of 1.6 µg/mL [92].
Acanthomanzamines A (114) and B (115), isolated from A. ingens,
contain a tetrahydroisoquinoline ring system instead of
β-carboline. Compounds 114 and 115 showed potent cytotoxicity
against HeLa cells, with IC50 values of 4.2 and 5.7 µM,
respectively. Interestingly, 114 and 115 (Figure 12) exhibited
stronger cytotoxicity against HeLa cancer cell line, but less
potent proteasome inhibitory activity than their co-isolated
β-carboline-containing manzamines, acanthomanzamines D and E [93].
Several other examples of β-carboline-based manzamines were also
reported from different sponge species. Examples of these are
pre-neo-kauluamine (116) from A. ingens [94], zamamidine C (117)
[95], zamamidine D (118) [96], nakadomarin A (119) from Amphimedon
sp. [97], ircinol A (120) from Amphimedon sp. [98], ircinal A (121)
from Ircinia sp. [86], ircinal E (122) from A. ingens [99], and
12,28-oxaircinal A (123) from Acanthostrongylophora sp. [100]. The
reported biological activities of the aforementioned compounds were
quite interesting, Compound 116 showed proteasome inhibitory
activity [94], whereas 117 displayed potent antitrypanosomal effect
against Trypanosoma brucei brucei and antimalarial activity against
P. falciparum [95]. Compound 118 exhibited antimicrobial activity
against several strains of fungi and bacteria [96], whereas 119
exhibited antimicrobial effects against C. xerosis and Trichophyton
mentagrophytes, with MIC values of 11 and 23 µg/mL, respectively
[97]. Compound 120 inhibited
Mar. Drugs 2020, 18, 368 19 of 34
endothelin-converting enzyme, with an IC50 of 55 µg/mL [98].
Compound 121 displayed cytotoxicity against L1210 and KB cancer
cells with IC50 values of 1.4 and 4.8 µg/mL, respectively [86].
Compound 122 showed weak cytotoxicity and L5178Y (murine lymphoma)
cells with an IC50 value of 21.7 µg/mL, respectively [99].
Pentacyclic manzamines having a ketonic group in their
eight-membered ring instead of a double bond were also reported.
Examples of this class of compounds are manzamines E (124) [76], F
(keramamine B) (125) from Xestospongia sp. [101], ent-manzanine F
(126) from Petrosia sp. [90], ent-12,34-oxamanzamines E (127) and F
(128) from the sponge 011ND 35 [89], 12,34-oxamanzamine E (129) and
6-hydroxymanzamine E (130) from Acanthostrongylophora sp. [77],
12,28-oxamanzamine E (131) and 12,34-oxa-6-hydroxymanzamine E (132)
from Acanthostrongylophora sp. [100], and the related manzamine
alkaloid 31-keto-12,34-oxa-32,33-dihydroircinal A (133) from the
marine sponge of the genus 011ND 35 [91] (Figure 12). Compounds 124
and 125 displayed cytotoxicity toward L5178Y cells, with ED50
values of 6.6 and 2.3 µg/mL), respectively [92], whereas they
showed similar significant cytotoxicity against P388 cells with an
IC50 value of 5.0 µg/mL [101]. Compound 126 inhibited M.
tuberculosis (H37Rv) with an IC50 < 12.5 µg/mL [90]. Compound
127 showed weak inhibitory activity against M. tuberculosis with an
IC50 value of 128 µg/mL, whereas 128 showed significant activity
with IC50 12.5 µg/mL [89].
Mar. Drugs 2020, 18, x FOR PEER REVIEW 20 of 36
instead of a double bond were also reported. Examples of this class
of compounds are manzamines E (124) [76], F (keramamine B) (125)
from Xestospongia sp. [101], ent-manzanine F (126) from Petrosia
sp. [90], ent-12,34-oxamanzamines E (127) and F (128) from the
sponge 011ND 35 [89], 12,34- oxamanzamine E (129) and
6-hydroxymanzamine E (130) from Acanthostrongylophora sp. [77],
12,28- oxamanzamine E (131) and 12,34-oxa-6-hydroxymanzamine E
(132) from Acanthostrongylophora sp. [100], and the related
manzamine alkaloid 31-keto-12,34-oxa-32,33-dihydroircinal A (133)
from the marine sponge of the genus 011ND 35 [91] (Figure 12).
Compounds 124 and 125 displayed cytotoxicity toward L5178Y cells,
with ED50 values of 6.6 and 2.3 μg/mL), respectively [92], whereas
they showed similar significant cytotoxicity against P388 cells
with an IC50 value of 5.0 μg/mL [101]. Compound 126 inhibited M.
tuberculosis (H37Rv) with an IC50 < 12.5 μg/mL [90]. Compound
127 showed weak inhibitory activity against M. tuberculosis with an
IC50 value of 128 μg/mL, whereas 128 showed significant activity
with IC50 12.5 μg/mL [89].
Figure 12. Structures of 114–133.
Figure 12. Structures of 114–133.
Mar. Drugs 2020, 18, 368 20 of 34
2.6.2. Tetracyclic Manzamines
Several manzamines containing a β-carboline ring system linked to a
tetracyclic scaffold have been reported. For example, manzamine B
(134) was reported from Haliclona sp. [102], manzamines H (135) and
J (136) were isolated from Ircinia sp. [86], manzamine J N-oxide
(137) was reported from X. ashmorica [92], 8-hydroxymanzamine B
(138) was reported from Acanthastrongylophora sp. [100], manzamine
L (139) was published from Amphimedon sp. [103], manzamine B
N-oxide (140), 3,4-dihydromanzamine B N-oxide (141) and
11-hydroxymanzamine J (142) were reported from
Acanthastrongylophora sp. [104], ma’eganedin A (143) was isolated
from Amphimedon sp. [105], 8-hydroxymanzamine J (144) was reported
from Acanthastrongylophora sp. [77], 3,4-dihydromanzamine J (145)
was isolated from Amphimedon sp. [87], acanthomanzamine D (146) and
acanthomanzamine E (147) were reported from A. ingens [93],
zamamidines A (148) and B (149) were reported from Amphimedon sp.
[106], ircinal B (150) was published from Ircinia sp. [86], and
ircinol B (151) was reported from Amphimedon sp. [98] (Figure
13).
Mar. Drugs 2020, 18, x FOR PEER REVIEW 22 of 36
N N H
HN N H
H 1 N N
H
N
HN
H
OHH
136: R1 = H, R2 = NO 137: R1 = H, R2 = O 144: R1 = OH, R2 =
NO
R2 R1
O
2.6.3. Monomacrocycle Containing Manzamines and Related
Compounds
Compounds in this group have one macrocyclic ring of different
sizes, namely, 10-, 11-, 13-, 14- and 15-membered rings. Manzamine
C (152) was initially isolated from the Okinawan sponge Haliclona
sp. This compound possesses an 11-membered heterocyclic ring
containing a nitrogen atom [102]. Compound 152 exhibited
cytotoxicity against A549, HT-29, and P-388 cells with IC50 values
of 3.5, 1.5, and 2.6 μg/mL, respectively [107]. The other manzamine
alkaloids containing one macrocyclic ring are keramamine C (153)
[108], acanthomanzamine C (154) [93], kepulauamine A (155) [104],
acantholactam (156) [94], and acantholactone (157) [109] (Figure
14). Compound 153 was isolated from the Okinawan marine sponge
Amphimedon sp. [108] and was probably a biogenetic precursor of
152. Compound 154 was isolated from A. ingens [93] and was recorded
as one of the first examples of a manzamine-related alkaloid
containing a tetrahydroisoquinoline ring system rather than a β-
carboline moiety. The hexahydrocyclopenta [b]-pyrrol-4(2H)-one ring
in 154 could have originated from an eight-membered ring in
manzamine A (97). Compound 155 was isolated from an Indonesian
marine sponge, Acanthostrongylophora sp. This compound contains a
pyrrolizine ring system, which is unique among the manzamines. It
exhibited weak inhibition against K562 (human erythroleukemic) and
A549 cells and is moderately active against diverse strains of
pathogenic bacteria. However, this compound is inactive against
sortase A (SrtA) and Na+/K+-ATPase [104]. Compound 156 was isolated
from A. ingens and contains a γ-lactam ring with a 2Z-hexenoic acid
substituent on the nitrogen atom and is proposed to be
biosynthetically derived from compound 97. It shows no proteasome
inhibitory activity [94].
Acantholactone (157), a manzamine-related scaffold with unique
δ-lactone and ε-lactam rings, was reported from
Acanthostrongylophora sp. The absolute configurations of the
stereogenic carbons
Figure 13. Structures of 134–151.
Compounds 135, 136, 139, 143, 145, 150, and 151 showed cytotoxic
activity against L1216 cancer cell line with IC50 values of 1.3,
2.6, 3.7, 4.4, 5.0, 1.9, and 7.7 µg/mL, respectively. Furthermore,
135, 136, 139, 150, and 151 displayed cytotoxicity against KB
cancer cells with IC50 values of 4.6, >10, 11.8, 3.5, and 9.4
µg/mL, respectively, whereas 137 showed cytotoxicity against L1578Y
with IC50 values of 1.6 µg/mL, and 148 and 149 showed cytotoxic
activity against P388 cells with IC50 values of 13.8 and 14.8
µg/mL, respectively. Compounds 146 and 147 displayed a strong
proteasome inhibitory effect, with IC50 values of 0.63 and 1.5
µg/mL, respectively [93]. Compounds 139 and 140 showed weak
activity against several Gram-positive and Gram-negative bacteria
[104]. Compound 143 showed potent activity against Sarcina lutea
and B. subtilis, with the same MIC value of 2.8 µg/mL [105]. The
reported antimicrobial activity of several manzamines highlights
the influence of an eight-membered ring on
Mar. Drugs 2020, 18, 368 21 of 34
the activity [77]. Moreover, the antitubercular activity is also
affected by the ring size; for example, compounds 97 and 136 have
similar scaffold, except eight-membered ring in 97 and 11-membered
in 136 [83]. Compound 97 exhibited potent anti-tubercular activity
against M. tuberculosis (H37Rv) than 136 [83].
2.6.3. Monomacrocycle Containing Manzamines and Related
Compounds
Compounds in this group have one macrocyclic ring of different
sizes, namely, 10-, 11-, 13-, 14- and 15-membered rings. Manzamine
C (152) was initially isolated from the Okinawan sponge Haliclona
sp. This compound possesses an 11-membered heterocyclic ring
containing a nitrogen atom [102]. Compound 152 exhibited
cytotoxicity against A549, HT-29, and P-388 cells with IC50 values
of 3.5, 1.5, and 2.6 µg/mL, respectively [107]. The other manzamine
alkaloids containing one macrocyclic ring are keramamine C (153)
[108], acanthomanzamine C (154) [93], kepulauamine A (155) [104],
acantholactam (156) [94], and acantholactone (157) [109] (Figure
14). Compound 153 was isolated from the Okinawan marine sponge
Amphimedon sp. [108] and was probably a biogenetic precursor of
152. Compound 154 was isolated from A. ingens [93] and was recorded
as one of the first examples of a manzamine-related alkaloid
containing a tetrahydroisoquinoline ring system rather than a
β-carboline moiety. The hexahydrocyclopenta [b]-pyrrol-4(2H)-one
ring in 154 could have originated from an eight-membered ring in
manzamine A (97). Compound 155 was isolated from an Indonesian
marine sponge, Acanthostrongylophora sp. This compound contains a
pyrrolizine ring system, which is unique among the manzamines. It
exhibited weak inhibition against K562 (human erythroleukemic) and
A549 cells and is moderately active against diverse strains of
pathogenic bacteria. However, this compound is inactive against
sortase A (SrtA) and Na+/K+-ATPase [104]. Compound 156 was isolated
from A. ingens and contains a γ-lactam ring with a 2Z-hexenoic acid
substituent on the nitrogen atom and is proposed to be
biosynthetically derived from compound 97. It shows no proteasome
inhibitory activity [94].
Acantholactone (157), a manzamine-related scaffold with unique
δ-lactone and ε-lactam rings, was reported from
Acanthostrongylophora sp. The absolute configurations of the
stereogenic carbons of 157 were determined as 12S, 24R, 25R, and
26R by comparison of calculated and experimental electronic
circular dichroism (ECD) spectra [109].
32,33-Dihydro-31-hydroxymanzamine A (158),
32,33-dihydro-6-hydroxymanzamine A-35-one (159), and
32,33-dihydro-6,31-dihydroxymanzamine A (160) were isolated from an
unidentified Indonesian sponge [110]. Compounds 158 and 159 showed
no effect against malaria and leishmanial [110]. Rao et al.
reported that the decrease of antimalarial activity is attributed
to the reduction of the C32-C33 double bond and oxidation of C31
[110].
Manzamine X (161) was reported from Xestospongia sp. Compound 161
exhibited cytotoxic activity against KB cells, with an IC50 value
of 7.9 µg/mL [111].
6-Deoxymanzamine X (162) was isolated from Xestospongia ashmorica
[92]. Compound 162 showed cytotoxicity against the L5178 cells with
ED50 value of 1.8 µg/mL, and exhibited a growth-inhibitory effect
against Spodoptera littoralis larvae with a percentage of lethality
of 18.8% at a dose of 132 ppm [92].
Manadomanzamines A (163) and B (164) were reported from the
Indonesian sponge, Acanthostrongylophora sp. [112]. These compounds
exhibited tubercular effect against Mycobacterium tuberculosis,
with MIC values of 1.9 and 1.5 µg/mL, respectively. Rifampin was
used as a control and showed tubercular effect with MIC values of
0.16 µg/mL. Compounds 163 and 164 showed cytotoxic activity against
HIV-1, with EC50 values of 7.0 and 16.5 µg/mL, respectively.
Compound 163 was cytotoxic against A-549 and HCT-116 cells, with
IC50 values of 2.5 and 5.0 µg/mL, respectively, whereas 164 was
cytotoxic against HCT-116, with an IC50 value of 5.0 µg/mL.
Compounds 163 and 164 were not cytotoxic against the normal Vero
cell line at a concentration of 4.8 µg/mL. Compound 164 exhibited
antifungal effect against Cryptococcus neoformans, with MIC value
of 3.5 µg/mL, whereas 163 exhibited antifungal activity against
Candida albicans with MIC value of 20 µg/mL [112].
Mar. Drugs 2020, 18, 368 22 of 34
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Figure 14. Structures of 152–166.
2.6.4. Structure–Activity Relationship (SAR) of Manzamine
Derivatives on Antimalarial Activity
Manzamines exhibited potent antimalarial activity due to their
multifunctionality scaffold. Thus, an overview of the
structure–activity relationships (SARs) of manzamines as
antimalarial agents can be summarized. The presence of β-carboline
and pentacyclic ring systems played an important role in the
antimalarial activities. The absence of these rings, for example in
iricinal scaffold, led to decreasing the antimalarial activity. 9-N
alkylation of the β-carboline ring led to decreasing antimalarial
activity, whereas 9-NH increased the activity. Hydroxyl group
substitution of the β-carboline ring, particularly position 8,
exhibited no effect as antimalarial. Substitution of the nitro or
methoxy groups at position 6 led to slight effects as antimalarial,
while it was retained upon substitution of a methyl ester at
position 3 of the β-carboline. The conformational of β-carboline
played a vital role in antimalarial activity of manzamines.
Modification of the planarity of β-carboline by changing pyridine
into piperidine and 2-N-methylation led to reduction of
antimalarial activity. An amide substitution on positions 8 and 6
of the β-carboline ting system reduced antimalarial activity. A
2-N-oxide derivative of manzamine A reserves its antimalarial
potency, whereas 2-N- methylation of manzamine A decreased
antimalarial potency against D6 and W2 strains, respectively. The
hydroxyl group at C-12 was essential for antimalarial activity. The
structure of manzamine F was connected to the potent antimalarial
effect of 8-hydroxymanzamine-A, with a carbonyl group at C- 31 and
a reduced C-32 double bond, exhibiting a reduction in antimalarial
activity. Modification of
Figure 14. Structures of 152–166.
Keramaphidin B (165), an unprecedented pentacyclic manzamine, was
isolated from Amphimedon sp. (Figure 14). Compound 165 exhibited
cytotoxic effect against P-388 and KB cells, with IC50 values of
0.28 and 0.3 µg/mL, respectively [113].
Kauluamine (166), a manzamine dimer, was isolated from the
Indonesian sponge Prianos sp. [114]. Compound 166 exhibited a
moderate immunosuppressive effect in a mixed lymphoma reaction
[114].
2.6.4. Structure–Activity Relationship (SAR) of Manzamine
Derivatives on Antimalarial Activity
Manzamines exhibited potent antimalarial activity due to their
multifunctionality scaffold. Thus, an overview of the
structure–activity relationships (SARs) of manzamines as
antimalarial agents can be summarized. The presence of β-carboline
and pentacyclic ring systems played an important role in the
antimalarial activities. The absence of these rings, for example in
iricinal scaffold, led to decreasing the antimalarial activity. 9-N
alkylation of the β-carboline ring led to decreasing antimalarial
activity, whereas 9-NH increased the activity. Hydroxyl group
substitution of the β-carboline ring, particularly position 8,
exhibited no effect as antimalarial. Substitution of the nitro or
methoxy groups at position 6 led to slight effects as antimalarial,
while it was retained upon substitution of a methyl ester at
position 3 of the β-carboline. The conformational of β-carboline
played a vital role in antimalarial activity of manzamines.
Modification of the planarity of β-carboline by changing pyridine
into piperidine and 2-N-methylation led to reduction of
antimalarial activity. An amide substitution on positions 8 and 6
of the β-carboline ting system reduced antimalarial activity. A
2-N-oxide derivative of manzamine A reserves its antimalarial
potency, whereas 2-N-methylation of manzamine A decreased
antimalarial
Mar. Drugs 2020, 18, 368 23 of 34
potency against D6 and W2 strains, respectively. The hydroxyl group
at C-12 was essential for antimalarial activity. The structure of
manzamine F was connected to the potent antimalarial effect of
8-hydroxymanzamine-A, with a carbonyl group at C-31 and a reduced
C-32 double bond, exhibiting a reduction in antimalarial activity.
Modification of the C-31 C=O to a hydrazone and alkylation greatly
improves the antimalarial effect. Reduction of the carbonyl group
at position 31 or introduction of a double bond in conjugation with
the carbonyl group (C-31) showed no antimalarial activity. A double
bond at carbon-31 in an eight-membered ring was required to
maintain the integrity of the ring system and thereby played an
important role in contributing to antimalarial activity. Saturation
of the double bond at C-31 affects the integrity of the ring and
resulting in a significant reduction in antimalarial activity,
while a successive reduction of the double bond at C-15 increases
antimalarial activity [83].
2.7. Macrocycles Containing 3-Alkyl Pyridinium Salts
2.7.1. Cyclostellettamines
Cyclostellettamines A–F (167–172) were reported from Stelletta
maxima [115] and Pachychalina sp. [8]. Cyclostellettamines G–I
(173–175), K (176), and L (177) were isolated from the marine
sponge Pachychalina sp. [8] (Figure 15). Compounds 167–177
exhibited antimicrobial activity against Candida albicans ATCC
10231, S. aureus ATCC 25923, Pseudomonas aeruginosa strain P1, E.
coli ATCC 25922, P. aeruginosa ATCC 27853 (strain Pa),
oxacillin-resistant S. aureus, and oxacillin-resistant S. aureus,
whereas 168, 169, 173, and 177 showed potent activity against M.
tuberculosis H37Rv (MtH37Rv) [116]. Cyclostellettamine C (169) was
the most potent antimicrobial activity among all investigated
Cyclostellettamines. With the exception of E. coli ATCC 25922 (Ec)
and S. aureus ATCC 25923 (Sa), the antimicrobial activity of these
cyclostellettamines is suggested to be influenced by the size of
the alkyl chains [116]. Dehydrocyclostellettamines D (178), E
(179), and cyclostellettamine G (173) were reported from the sponge
of the genus Xestospongia [117]. These compounds showed moderate
inhibitory activity against histone deacetylase from K562 cells
with IC50 values of 17, 30, and 80 µM. Compounds 178, 179, and 173
exhibited cytotoxic activities against P388 cells with IC50
values of 1.3, 1.3, and 2.7 µM; against HeLa cells with IC50 values
of 0.60, 1.8, and 2.8 µM; and against 3Y1 (rat fibroblastic cells)
IC50 values of 4.3, 3.2, and 11 µM [117], respectively. Xu et al.
isolated 8,8′-dienecyclostellettamine (180) from the sponge
Amphimedon compressa. 180 exhibited strong potent antibacterial
activity [118].
Cyclostellettamines N (181), R (182), O (183), and Q (184) were
reported from Haliclona viscosa [119]. Eight cyclostellettamine
derivatives (185–192) were reported from Haliclona sp., without
given specific names [120]. Compounds 181 and 184–192 exhibited
moderate cytotoxicity against A549 cancer cell lines, whereas 184,
186, and 190–192 showed strong antibacterial activity against a
number of Gram-positive and Gram-negative bacteria [120]. Lee et
al. studied the effect of degree of saturation, the length of the
alkyl chains, and the double-bond locations effects on the
biological activities of the compounds 184, 186, and 190–192, and
they found that the biological activities were influenced by (i)
the length of the alkyl chains, (ii) the distance between the
charged groups, and (iii) the electron-rich locations [120].
In 2017, cyclostellettamine P (193) with C9 and C11 alkyl chains
was detected by ion mobility–mass spectrometry [121] (Figure
15).
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Mar. Drugs 2020, 18, x FOR PEER REVIEW 26 of 36
Figure 15. Structures of 167–196.
Cyclostellettamines N (181), R (182), O (183), and Q (184) were
reported from Haliclona viscosa [119]. Eight cyclostellettamine
derivatives (185–192) were reported from Haliclona sp., without
given specific names [120]. Compounds 181 and 184–192 exhibited
moderate cytotoxicity against A549 cancer cell lines, whereas 184,
186, and 190–192 showed strong antibacterial activity against a
number of Gram-positive and Gram-negative bacteria [120]. Lee et
al. studied the effect of degree of saturation, the length of the
alkyl chains, and the double-bond locations effects on the
biological activities of the compounds 184, 186, and 190–192, and
they found that the biological activities were influenced by (i)
the length of the alkyl chains, (ii) the distance between the
charged groups, and (iii) the electron-rich locations [120].
In 2017, cyclostellettamine P (193) with C9 and C11 alkyl chains
was detected by ion mobility– mass spectrometry [121] (Figure
15).
2.7.2. Njaoaminiums
Cyclic 3-alkylpyridinium salts, njaoaminiums A (194), B (195), and
C (196) are alkylpyridinium salts (proposed to be the precursor of
njaoamine alkaloids) reported from Reniera sp. [122] (Figure 15).
Compound 195 exhibited growth inhibitory activity against
MDA-MB-231, A549, HT29 with GI50 values of 4.8, 4.1, and 4.2 μM
[122].
2.8. Motuporamines
Motuporamines A-C (197-199) (Figure 16) [123], were isolated from
the marine sponge X. exigua. Later on, three new motuporamines D–F
(200-202), a mixture of motuporamines G–I (203-205) (Figure 16)
along with compounds 197–199, were isolated from the same marine
sponge [124]. This subclass was characterized by the presence of a
saturated macrocyclic ring of the 13 to 15 carbons and two basic
nitrogen atoms in the linear side chain. Compounds 197–199 and
203–205 exhibited significant anti-invasion effects, with IC50
values less than 15 μM, whereas no anti-invasion activity was shown
by 200 and 201 [124]. The SARs explained the importance of the
saturated 15-
Figure 15. Structures of 167–196.
2.7.2. Njaoaminiums
Cyclic 3-alkylpyridinium salts, njaoaminiums A (194), B (195), and
C (196) are alkylpyridinium salts (proposed to be the precursor of
njaoamine alkaloids) reported from Reniera sp. [122] (Figure 15).
Compound 195 exhibited growth inhibitory activity against
MDA-MB-231, A549, HT29 with GI50
values of 4.8, 4.1, and 4.2 µM [122].
2.8. Motuporamines
Motuporamines A-C (197–199) (Figure 16) [123], were isolated from
the marine sponge X. exigua. Later on, three new motuporamines D–F
(200–202), a mixture of motuporamines G–I (203–205) (Figure 16)
along with compounds 197–199, were isolated from the same marine
sponge [124]. This subclass was characterized by the presence of a
saturated macrocyclic ring of the 13 to 15 carbons and two basic
nitrogen atoms in the linear side chain. Compounds 197–199 and
203–205 exhibited significant anti-invasion effects, with IC50
values less than 15 µM, whereas no anti-invasion activity was shown
by 200 and 201 [124]. The SARs explained the importance of the
saturated 15-membered cyclic amine, which fused to the
motuporamines diamine side chain, as the required structure for
anti-invasive effects [124].
Mar. Drugs 2020, 18, 368 25 of 34
Mar. Drugs 2020, 18, x FOR PEER REVIEW 27 of 36
membered cyclic amine, which fused to the motuporamines diamine
side chain, as the required structure for anti-invasive effects
[124].
Figure 16. Structures of 197–205.
3. Biosynthetic Considerations
Densanin A (1) was a unique alkaloid and was characterized by a
hexacyclic diamine skeleton with two long chains. Figure 17 shows a
plausible biosynthetic pathway of densanin A from 3- alkylpyridine,
as proposed by Baldwin and Whitehead [125].
Cimino et al. proposed that bis-3-alkylpiperidine was the building
block of xestospongins, petrosins, and saraines [40,126]. They
indicated that there was a biosynthetic relationship between the
oligomeric halitoxins and the three macrocyclic alkaloids. Another
study indicated a detailed hypothetical pathway for the formation
of araguspongines, petrosins, and aragupetrosine A in the marine
sponge Xestospongia sp. [19,126]. A smart study revealed the
relationship between manzarnines and xestospongins, petrosins, and
saraines [40]. Baldwin and Whitehead provided the first suggestion
about the biogenetic origin of piperidine ring and foresaw the
occurrence of ircinal A (121) and B (150) and ingenamine alkaloids
(Figure 18) [39,126]. Subsequently, three studies indicated the
generation of the hypothetical pathways to halicyclarnine, saraines
1–3, saraines A–C, and madangarnine skeletons [39,126].
Figure 16. Structures of 197–205.
3. Biosynthetic Considerations
Densanin A (1) was a unique alkaloid and was characterized by a
hexacyclic diamine skeleton with two long chains. Figure 17 shows a
plausible biosynthetic pathway of densanin A from 3-alkylpyridine,
as proposed by Baldwin and Whitehead [125].
Mar. Drugs 2020, 18, x FOR PEER REVIEW 28 of 36
Figure 17. Plausible biosynthetic pathway of densanin A.
The three basic building blocks of the biosynthesis of
3-alkylpiperidine alkaloids manzamine C (152), keramaphidin C (165
A), and keramamine C (153) include ammonia, a propenal and a
variable chain of saturated or unsaturated linear dialdehyde
[75,127,128].
The cross-electrophilic reaction between an equivalent of ammonia
with a propenal unit and one terminus of the linear dialdehyde led
to a formation of dihydropyridine, with a linear alkyl aldehyde
attached at the position 3. Oxidation of the dihydropyridine ring,
condensation of the free aldehyde functionality with ammonia,
methoxy amine, or simple alkyl amines followed by oxidative or
reductive transformations of the resulting imine led directly to
monomeric 3-alkylpiperidines [75,85,129].
Chain extension occurred if the aldehyde functionality undertook
reductive condensation with ammonia, another equivalent of
propenal, and a terminus of another dialdehyde chain to afford a
dimer with a second dihydropyridine system. Multiple replications
of the elongation sequence were necessary to generate halitoxins.
Cyclization involved condensation of the terminal aldehyde
functionality at one end of the oligomer and the amino nitrogen in
the dihydropyridine ring on the other terminus of the oligomer
[129].
Cyclostellettamines result from the oxidation of the
dihydropyridine rings containing appropriate linear alkyl bridges,
while haliclamines result from reduction of the dihydropyridine
rings. Two dialdehydes of 11 carbon atoms were required for the
biogenesis of a hypothetical macrocyclic precursor of
xestospongins, petrosins, araguspongines, and aragupetrosines.
Oxidation of the alkyl chains to afford the diketo-macrocycle
intermediate, followed by carbocyclic or heterocyclic ring
formation generated either the quinolizidine or the
1-oxaquinolizidine ring systems found in the petrosins,
xestospongins, araguspongines, and aragupetrosines [19].
Additionally, transformations including methylation and
hydroxylation are common in the biosynthesis of petrosins,
xestospongins, and araguspongines [46].
The pentacyclic skeleton of ingenamine alkaloids arose from a
biological intramolecular [4 + 2] cycloaddition reaction between
the tautomeric forms of the two dihydropyridine rings in a bis-3-
alkyldihydropyridine macrocycle. The initial [4 + 2] adduct
intermediate underwent redox exchange to obtain the pentacyclic
intermediate. Hydrolysis of the iminium ion functionality led to a
tetracyclic seco-skeleton with aldehyde functionality. The skeleton
and the aldehyde functionality correspond exactly to the skeleton
and aldehyde functional group in ircinal A (121). The condensation
of the ircinal-type intermediate with tryptamine and oxidation of
the resulting product led to manzarnine B (134) (Figure 18).
Ingenamine-type intermediates were suggested as the precursors of
halicyclamine A and madangamines. This can be performed through a
cleavage of the C-18 and C–33 bond in the ingenarnine-type
intermediate, which gives rise to the halicyclamine scaffold [129].
This biogenetic hypothesis was used to assign the relative
stereochemistry at C-3 and C-l9 in halicyclamine A (77).
Cyclization to form a quinolizidine ring system transforms a
halicyclamine-type intermediate into the saraine-1 to -3 scaffold
[9]. Investigation of saraine A revealed that disconnection of the
C2-C3
Figure 17. Plausible biosynthetic pathway of densanin A.
Cimino et al. proposed that bis-3-alkylpiperidine was the building
block of xestospongins, petrosins, and saraines [40,126]. They
indicated that there was a biosynthetic relationship between the
oligomeric halitoxins and the three macrocyclic alkaloids. Another
study indicated a detailed hypothetical pathway for the formation
of